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Cyclophosphamide/etoposide in pediatric B-ALL
and delayed intensification phases of therapy to improve the DFS in the VHR subgroup. Two intensification strate- gies were tested in AALL1131 and compared to the control arm. The first intensification strategy included the combi- nation of clofarabine with cyclophosphamide/etoposide, a promising combination in relapsed ALL23,24 (experimental arm 2) and cyclophosphamide/etoposide without clofara- bine (experimental arm 1). This began as a 1:2:2 random- ization between the control arm and experimental arms 1 and 2, respectively. Experimental arm 2, testing clofara- bine, was found to be too toxic and not feasible when given in this combination to newly diagnosed patients with VHR B-ALL, and this arm of AALL1131 was, there- fore, closed to further accrual in September 2014.7 AALL1131 thus continued as a two-arm study comparing the control arm with experimental arm 1 in a 1:2 random- ized fashion. This randomization was later stopped for futility when the interim monitoring boundary was crossed, identifying non-superiority of DFS when consol- idation and delayed intensification included cyclophos- phamide/etoposide compared to standard VHR therapy (modified augmented Berlin-Frankfurt-Münster regimen). With additional follow-up after closure of the randomiza- tion, there was even stronger evidence that experimental arm 1 would never be superior to the control arm with the reported DFS being 85.5±6.8% for the control arm compared to 72.3±6.3% for experimental arm 1 (P=0.76). The 4-year DFS of 85.5±6.8% reported for the control arm of this study was higher than the 70% we originally predicted based on data available for patients with VHR features treated in the preceding B-ALL studies for stan- dard-risk (AALL0331) and high-risk (AALL0232) patients. Many patients in these earlier studies did not receive high-dose methotrexate during interim maintenance-1 which may have resulted in the differences in the DFS rates we report. Additionally, the definitions of VHR were expanded in AALL1131 to include groups of patients at least 13 years of age as well as lower minimal
residual disease thresholds which may also have con- tributed to differences in the DFS we observed.
In summary, intensification of cytotoxic chemotherapy by substituting either clofarabine/cyclophosphamide/ etoposide or cyclophosphamide/etoposide for cyclophos- phamide/cytarabine/6-mercaptopurine (or 6-thioguanine) during part 2 of consolidation and delayed intensification did not improve DFS compared to that of patients receiving standard COG VHR therapy in this study. Future therapeu- tic studies for pediatric patients with VHR B-ALL could pur- sue immunologically and/or molecularly targeted therapies which may have more potential to improve outcomes than further intensification of cytotoxic chemotherapy.25-27 In this regard, the COG is currently investigating the tyrosine kinase inhibitor dasatinib for newly diagnosed high-risk patients with Philadelphia-like B-ALL harboring ABL-class lesions (AALL1131, NCT02883049) and ruxolitinib for newly diagnosed NCI-HR patients with Philadelphia-like B- ALL harboring CRLF2 rearranged and/or JAK pathway mutated B-ALL (AALL1521, NCT02723994). Additionally, the COG plans to bring both inotuzumab ozogamicin (humanized monoclonal antibody against CD22) and blina- tumomab (anti-CD19/CD3 bispecific T-cell engager anti- body) into the next generation of upfront studies for high- risk and standard-risk B-ALL, respectively, anticipated to open in 2019.
Acknowledgments
This trial was supported by grants U10 CA98543, U10 CA98413, U10 CA180886, U10 CA180899 from the National Institutes of Health and supported by St. Baldrick’s Foundation. LG is the Ergen Family Chair in Pediatric Oncology at the Children’s Hospital of Colorado. EAR is a KiDS of NYU Foundation Professor at NYU Langone Health. MLL is the UCSF Benioff Chair of Children’s Health and Deborah and Arthur Ablin Endowed Chair in Pediatric Molecular Oncology. SPH is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics at The Children's Hospital of Philadelphia.
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